Altered kynurenine pathway metabolism in autism: Implication for immune‐induced glutamatergic activity

Abstract

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

“…If one assumes that this increased genetic potential translates into an increased tryptophan metabolization, this finding is in line with previous research and is of particular interest as L-tryptophan, the precursor for serotonin, is decreased in PD patients’ brains. L-tryptophan is also metabolized to kynurenines, whereof metabolites have regulatory immune function and were described as either harmful or beneficial in PD [79–81]. Urinary metabolomics profiling demonstrated significant changes of urinary markers including an increased tryptophan metabolism, which was associated with the progression of PD [82].…”

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

“…Notably, it has been amply documented that therapeutic administration of IFN-α can induce depression, leading Wichers et al to propose that IDO1 induction (and consequent neurotoxicity) was the principal pathophysiological mechanism 17 . Regarding autism, independent cohort studies have documented dysregulation of KYN metabolism in patients diagnosed with autism spectrum disorder 59,60 , as demonstrated by increased KYN/kynurenic acid ratios 60 and elevated levels of QA 59 . The higher prevalence of autism in people with DS, coupled to our finding of increased levels of KYN in plasma from people with DS, support the growing notion of neuroinflammatory processes in the etiology of autism spectrum disorders.…”

Kynurenine Pathway in Autism Spectrum Disorders in Children

“…However, only a few studies have examined the KYN pathway in children with an ASD diagnosis. Lim et al [40] found no significant differences in KA levels between children with newly diagnosed ASD in 15 different Omani families and their age-matched healthy siblings ( n = 12). However, the ASD children exhibited significant lower levels of pic­olinic acid, which has well-described neuroprotective functions [41], while the QA level was significantly higher in the ASD patients than in the control group.…”